Chronic infection with hepatitis C virus (HCV) is a major public health problem, particularly in Egypt, where the prevalence of HCV infection is high. Among the long-term complications of HCV are hepatocellular carcinoma (HCC) and non-Hodgkin's lymphoma (NHL), but, particularly for NHL, few prospective studies have been done; hence, the incidence of malignant complications of chronic HCV is largely unknown. The contribution of other cancer risk factors also needs to be taken into account in assessing the HCV-associated risk of HCC and of NHL. Such factors include environmental exposures to carcinogens and inherited genetic susceptibilities, and new research is needed to investigate whether these risk factors can interact with HCV to modify the risks of malignancies in persons with chronic infections. In addition, the role of tumor suppressor genes in the biology of HCC and NHL cells needs to be addressed more fully. To fill these gaps in knowledge, this proposal builds upon an ongoing collaborative infrastructure of American and Egyptian scientists and research institutions to investigate the epidemiology of HCV- associated malignancies in Egypt. We propose to conduct: (1) a case-control study of the interrelationships among viral, genetic, and environmental risk factors for these two cancers; (2) a prospective study to estimate the incidence of HCC and NHL in persons with chronic HCV; and (3) a study of the mutational spectrum of the p53 gene in the tumor tissues of patients with HCC and NHL. Given the high prevalence of both HCV and HCV- related cancers in Egypt, the high potential for environmental exposures to carcinogenic chemicals there, and our demonstrated ability to collect biological samples and to obtain high-quality data from study subjects in Egypt, this proposal represents a unique opportunity to address important questions concerning the role of hepatitis C in these types of cancers.